Compositions and in situ methods for forming films on body tissue

ABSTRACT

A film-forming composition for topical application of medicaments to body tissues. The film-forming composition includes hydroxypropyl cellulose; a non-toxic volatile solvent for said hydroxypropyl cellulose and said reaction product, and an esterification agent which reacts with the hydroxypropyl cellulose to form a reaction product which is soluble in the solvent. The medicinal compound is selected from the group consisting of hydrocortisone, hydrocortisone acetate, betamethasone dipropionate, triamainolone acetonide, lidocaine hydrochloride, dibucaine hydrochloride.

This application is a continuation-in-part of my copending U.S.application Ser. No. 474,743, filed Mar. 8, 1990, (PCT/US89/032l6, filedJuly 24, 1989) which is, in turn, a continuation-in-part of my copendingInternational Application PCT/US88/02515 filed 25 July, 1988 which is,in turn, a continuation-in-part of my prior U.S. application Ser. No.189,032, filed May 2, 1988, now abandoned.

This invention relates to compositions and methods for in situ treatmentof body tissues.

In another respect, the invention pertains to the use of hydroxypropylcellulose (HPC) in the manufacture of such compositions and the use ofsuch compositions, manufactured from HPC.

According to another aspect, the invention relates to methods oftreating skin, mucosal tissue and other moist tissue, by forming anadherent film thereon.

In another respect, the invention relates to compositions and methodsfor forming films in situ on body tissues, which films are effectivesustained release carriers for medicinal and cosmetic components, tomaintain such medicaments at and on a treatment site on body tissue.

In the topical treatment of body tissue, problems are encountered inmaintaining treatment compositions in contact with the treatment site.The problem arises because normal movement of the treatment site andsurrounding tissue, as well as abrasion or irrigation of the treatmentsite, causes topical compositions to be displaced.

In the case of mucosal tissue, it is considered practically impossibleto maintain a treatment composition at the treatment site for more thana few minutes The mucosal tissues are glaborous and initially wet whichinterferes with attempts to adhesively secure a treatment composition tothese tissues.

The use of topical anesthetics for reducing pain is known. For example,commercially-available preparations containing benzocaine are widelyused. However, these do not form coherent films in the mouth and areeasily displaced from the ulcer site by saliva and physical movement ofthe surrounding tissues. An intra-oral ointment base for use in the oralcavity has been proposed which consists essentially of sodiumcarboxymethyl cellulose and pectin. However, such ointments are notconsidered sufficiently persistent to solve the basic problem ofmaintaining a topical analgesic agent in contact with an ulcer for up toseveral hours.

Topical adhesive dosages for mucosal ulcers have also been proposed inthe form of a two-phase tablet having an adhesive peripheral layer ofhydroxypropyl cellulose with the medication carried in an oleaginouscore of cocoa butter. This device adheres to the mucosa of dogs forthirty minutes to six hours.

Mixtures of hydroxypropyl cellulose (HPC) and polyvinylacetate have beenproposed as film-forming carriers for medications, but no use of suchsystems for intra-oral application of topical medicines has resulted.

Precast films of hydroxypropyl cellulose containing analgesics andantibiotics has been reported anecdotally for the treatment of pain ofleukoplakia.

Alkyl cellulose and/or cellulose ether compounds have been used asthickeners or ointment bases for a wide variety of medicaments. Forexample, an alkyl cellulose, believed to be methyl cellulose, was usedas a carrier and ointment base for the topical medicinal compositiondescribed in Tinnell U.S. Pat. No. 4,381,296. Hydroxyethyl celluloseand/or hydroxypropyl cellulose was used to form a gel for application ofthe topical acne medications of Boghosian et al. U.S. Pat. No.4,244,948. And a water-soluble film formed of hydroxypropyl cellulosewas used as the carrier for a bactericide in a teat-dip composition inMarks et al. U.S. Pat. No. 4,434,181.

Heretofore it was understood that the relief of pain associated withrecurrent aphthous stomatitis (RAS) ulcers was temporarily alleviated bythe medicinal composition of Tinnell '296 patent in analcohol-methylcellulose carrier. However, more recently, it has beendemonstrated that a principal analgesic effect is due to a protectivefilm which forms, which acts as a barrier to further insults of theulcer by foods, saliva, etc. Moreover, it is now understood that thebarrier film formation is due to chemical reaction of the medicinalcompositions of Tinnell '296 and the cellulosic thickener, rather thanby simple deposition of the cellulosic material per se, uponvaporization of the alcoholic solvent. Further, it has now beendiscovered that the cellulosic component of the commercially availablegels containing the Tinnell '296 medicaments is, in fact, hydroxypropylcellulose, rather than methylcellulose as previously understood.Finally, I have determined that the mechanism of film formation isspecific to hydroxypropyl cellulose. Closely related alkyl orhydroxyalkyl-substituted cellulose, such as methylcellulose,hydroxyethyl cellulose and hydroxybutyl cellulose are not suitable forHPC.

The barrier effect of the film derived from HPC provides practicallyinstantaneous and long-lasting substantial reduction of the painassociated with aphthous and other ulcers and trauma. This pain reliefand prevention activity by the barrier action of the film is verysurprising in view of the previous belief that it was necessary toprovide an analgesic, e.g., benzocaine, at the ulcer side.

I have further discovered that the compositions for forming theHPC-derived films in situ on body tissues can also function as stablecarriers for a wide variety of medicinal components. When suchcompositions are applied as a treatment to body tissue, the medicinalcomponents are incorporated in the resulting in situ formed films, fromwhich they are released to provide a sustained supply of the medicine atthe treatment site.

Briefly, in accordance with my invention, I use HPC in the manufactureof a film-forming composition for topical treatment of human tissue. Thecomposition comprises hydroxypropyl cellulose, an esterification agent,and a suitable volatile solvent which functions as a medium for reactionof the HPC and the acid and also to maintain the esterification reactionproduct in the form of a gel or lotion for convenient application. Suchcompositions are especially adapted to treatment of trauma of skin andmucosal tissue from external causes, e.g., cuts, abrasions, incisionsand burns, as well as bacterial and fungal infections and ulcers ofunknown etiology.

Advantageously, the solvent is alcoholic, e.g., ethyl, isopropyl ormethyl alcohol. The specific solvent is chosen for its ability todissolve the HPC and esterification agent and to maintain theesterification reaction product in solution or suspension untilapplication of the composition to the treatment site. Obviously, thesolvent should not be toxic to the body in the quantities employed.

The esterification agent can, advantageously, be a weak carboxylic acidwhich is substantially non-toxic. The specific acid or acids areselected for their ability to react with the HPC to form anesterification reaction product (see below) which is soluble in thereaction mixture at storage temperatures, e.g., 40-80 degreesFahrenheit, but which is insoluble in body fluids at or near bodytemperatures and above. Suitable weak organic acids include salicylicacid and tannic acid and mixtures thereof. Other suitable esterificationagents can be identified by those skilled in the art, having regard forthis disclosure.

According to another embodiment of the invention, I provide compositionswhich comprise the film-forming compositions described above and abiologically active topical treatment component, cosmetics, ormedication. The biologically active component is physically incorporatedin the film-forming components and in the film formed therefrom, toprovide medically effective quantities of the topical agent at thetreatment site on body tissue The incorporated biologically activecomponents are thus maintained in contact with the tissue for a timeeffective to treat the medical condition for which they are intended,rather than being displaced by physical movement of the tissue, abrasionor by irrigation by body fluids. There are indications that the filmsprovide a sustained release mechanism which increases the efficacy ofthe treatment The HPC derived films are inert and do not interfere withthe normal action of the topical treatment agent.

According to my present understanding, the esterification component ofthe compositions esterifies at least a portion of the HPC. Thisesterification reaction apparently takes place primarily upon drying ofthe solvent carrier. The HPC and acid components of my composition, aswell as any ester derivative which may form in solution prior toapplication of the composition to the body tissue are soluble in thesolvent carrier at room temperature under normal pre-application andstorage conditions. However, upon application of the compositions andair-drying of the solvent, with further esterification, a film is formedin situ which is insoluble in body fluids at and above normal bodytemperature of about 37 degrees Centigrade.

In a presently preferred embodiment of the invention, I also incorporatea non-toxic weak cross-linking agent in the compositions of theinvention. The resultant in situ formed film is somewhat tougher andmore resilient and has better adhesion to body tissue than such filmswhich are formed from compositions without such cross-linking agent. Theagents for cellulosic compounds, the specific agent being chosen so asto avoid premature formation of an insoluble mass prior to applicationof the composition. According to present knowledge, boric acid is anappropriately effective cross-linking agent for use in practicing thepresent invention. While I do not wish to be bound by this mechanism, itappears that the cross-linking agent effectively bonds some of theun-esterified hydroxyl groups into the film formed on drying of thecomposition after application to the body tissue. This belief is basedon the observation that without a cross-linking agent in thecomposition, two film layers may actually form upon drying of thesolvent, one of which is believed to be a film of the esterified HPC andthe other of which is a less tenacious film of un-esterified HPC.Presence of the cross-linking agent apparently bonds these two filmlayers resulting in a more tenacious, tough and durable film formed insitu on the body tissue.

The HPC-derived films are soluble in ethyl alcohol and similar non-toxicvolatile solvents, e.g., isopropyl alcohol and the like, but areinsoluble in water and water-containing body fluids, e.g., saliva atnormal human body temperature. Films formed by evaporation of thesolutions are tough, resilient and adhesive to body tissues and form aprotective barrier against air, other body fluids and foreignsubstances.

The cellulosic compound, which is reacted with weak carboxylic acids toform the film according to my invention, is selected for its ability toreact with the carboxylic acid component to form a film which isinsoluble in water and aqueous body fluids at a temperature equal to orgreater than body temperature. According to present knowledge,hydroxypropyl cellulose (HPC) is suitable. Such cellulosic compound isavailable commercially, for example, the product sold under the name"Klucel", a registered trademark of Aqualon Company. The type "MF"Klucel product is particularly suitable.

The solvent for forming the solutions of the HPC is selected for itsability to dissolve the HPC and HPC esters and its non-toxiccharacteristics when the composition is applied in the amount necessaryto form a protective film. For example, ethyl alcohol is preferred whenthe film is to be deposited in the oral cavity whereas isopropyl alcoholis suitable for use in depositing films on the skin. Other suitablesolvents will be readily identified by those skilled in the art having aregard for the disclosures herein, e.g., volatile polar solvents whichare medically compatible with body tissue.

The specific esterification agent component of the compositions ischosen for its ability to react with the HPC to form, upon air-drying ofthe composition, a tough resilient film which adheres to body tissue.Strong carboxylic acids, e.g., acetic acid, citric acid and the like donot provide this result. However, weak carboxylic acids, especiallysalicylic acid, tannic acid and the like and mixture thereof functioneffectively. The in situ film formation capability appears to be relatedto the solubility of the HPC derivative in water and aqueous body fluidsat body temperature. Hence, any such weak carboxylic acid which isnon-toxic and has the capability for form such insoluble films can beeffectively employed, the selection of such weak acid being within thecapability of persons skilled in this art, having regard for thisdisclosure. Salicylic acid and tannic acid have been identified asparticularly effective in the practice of my invention. In fact, it nowappears that a mixture of these two acids in the film formingcompositions of the invention produce a superior film in terms ofadhesion and mechanical integrity, although either of these acids aloneprovides an effective in situ deposited film.

The film of HPC which is formed by evaporation of the compositions isapparently a "physical film", i.e., the cellulosic compounds do notpolymerize. Evidence of the physical characteristics of these films isprovided by the fact that such film, once formed, simply re-dissolvesupon further application of the compositions to the same site.

The film forming composition can be applied to the body tissue by anyconvenient technique, e.g., spraying, dipping or simple directapplication by a swab.

According to the presently preferred embodiments of the invention, theHPC component is present in the solution in an amount from about 0.1-20%by weight of the final composition. The proportion of the HPC in thecomposition affects the time required for the composition to air dry andform the tough adhesive film. At lower contents of the HPC compound, thecomposition dries more slowly, but the resultant film is more coherentand abrasion-resistant. At higher contents, the film forms more quicklyby air drying, but the resultant film is less coherent and adhesiveowing to the fact that the portion of the film at the surface of theapplied composition and at the body tissue surface dries at differentrates.

At present, I prefer to employ some 0.1-10% by weight of HPC in thefinal composition, which provides an easily-applied gel, as distinctfrom a runny liquid. Best results are obtained with about 2.5% by weightof HPC in the gel composition. The carboxylic acid component of thecomposition can be a single acid, alone or in combination with otherweak carboxylic acids. Whether present alone or in combination, however,the proportion of the carboxylic acid can vary from about 1 to about 10%by weight of the composition with the optimum concentration being closerto the upper portion of this range. Indeed, there are indications thathigher proportions of the carboxylic acids do not appreciably interferewith the film formation. In the lower range, the film forms more slowlyand is less coherent.

The compositions are applied typically in localized areas, to the bodytissue and air-dried to form the film in situ, adhesively secured to thetissue. For best results, when applied to a wet or moist tissue, stepsshould be taken to remove as much of the water, moisture or other bodyfluids from the surface of the body tissue before applying thecomposition. For example, when applied inside the mouth, normal dentalprocedures for substantially drying the mucosal tissue are employed andair is drawn or blown over the surface of the applied composition topromote more rapid evaporation of the solvent and formation of the film.

The compositions have been found especially useful in the treatment ofaphthous ulcers of the mucosa, including recurrent aphthous stomatitis.This treatment provides essentially immediate and long-lasting relief ofthe exquisite pain associated with such ulcers in the formation andprelocalizing steps. The particular composition which has been foundmost effective in alleviating such pain, includes HPC, ethyl alcoholsolvent, a mixture of tannic and salicylic acids as the weak carboxylicacid component and boric acid as the cross-linking agent. Thecomposition is applied directly to the surface of the ulcer andsurrounding mucosa with a swab and is air dried by simply ensuring thatthe patient breathes normally through the mouth. The film is adhesivelyretained on the ulcer site and surrounding mucosal tissue for extendedperiods of time, upwards of several hours Furthermore, the initial painrelief, obtained by the exclusion of air, saliva, etc., from the ulcer,continues during this extended retention period and even preventsrecurrence of the pain despite repeated attempts to cause pain onset bydeliberately insulting the ulcer with irritating foods such as orangejuice.

EXAMPLE 1

A composition is prepared by mixing the following components in theindicated proportions:

    ______________________________________                                        Components         % (wt)                                                     ______________________________________                                        ethyl alcohol      87                                                         hydroxypropyl cellulose                                                                          2.5                                                        tannic acid        7.0                                                        salicylic acid     2.5                                                        boric acid         1.0                                                        ______________________________________                                    

EXAMPLE 2

The composition of Example 1 is tested for pain reduction capability incomparison with the commercially available medication sold under thename "Orabase", a composition containing benzocaine in a sodiumcarboxymethyl cellulose and pectin base.

Twenty otherwise healthy human subjects who suffer from recurrentaphthous stomatitis are separated into test and control groups of tenmembers each.

Comparable test sites consisting of an aphthous ulcer and surroundinghealthy mucosal tissue is selected in the mouths of each of thesubjects. These sites are prepared by irrigating with distilled waterand then carefully drying with cotton gauze pads.

The composition prepared according to this example is applied as a thincoating to the prepared aphthous ulcer sites in the mouths of the testgroup and a similar thin coating of the Orabase control medication isapplied to aphthous ulcer sites in the mouths of the control group.

The patients of both the test group and the control group are requiredto breathe normally through the mouth for a period of two minutes, afterwhich point it is noted that the composition of Example 1 has dried inthe mouths of the test group patients to form a film over the aphthousulcer site.

Observation of the test and control patients demonstrates that the filmsof the test composition are still present in place in 80% of the testsubjects' mouths two hours after application, whereas the controlmedication completely disappears from the ulcer sites in all subjects inthe control group.

EXAMPLE 3

The procedure of Example 2 is repeated except that, just prior to thepreparation of the ulcer sites, the aphthous ulcers in the mouths ofboth the test and control patients are insulted by application of orangejuice. The incidence of pain is clinically observed for a period of onehour, at which time the treated ulcer sites are once again insulted withorange juice. Pain observation is continued for an additional threehours.

In both the test and control groups, all patients experience a largeincrease in pain after the first insult, followed by a mild tosignificant decrease in pain after the immediate application of both thetest and control compositions.

At a second insult, the patients in the test group which are treatedwith the composition of the present invention experience no increase inpain and continue to experience mils to substantial pain reduction forthe succeeding three hours. However, the patients in the control groupexperience a large increase in pain at the second insult which decreasesonly slightly during the ensuing three hours.

EXAMPLE 4

The procedures of Examples 1-2 are repeated except that the compositionscontain, respectively, 10% tannic acid, 10% salicylic acid and 7% boricacid. Both of these compositions yield comparable results to those setforth in Examples 2 and 3.

EXAMPLE 5

The boric acid cross-linking agent is omitted from the compositions ofthe preceding Examples. The in situ deposited films formed from thesecompositions actually comprise two layers which can be mechanicallyseparated. Although these two-layer films are effective in paintreatment, they are less persistent.

EXAMPLE 6

Therapeutically effective quantities of various topical medicines areincorporated into the compositions of Example 1. The resulting mixturesare shelf-stable and are topically applied to body tissue and air-dried,forming resilient adherent films containing the medicaments, whichmigrate to the treatment site to effectively accomplish the desirestreatment.

Anesthetics

Benzocaine

Dycloninc hydrochloride

Hexylcaine hydrochloride

Pramoxine hydrochloride

Butamben picrate

Tetracaine hydroiodide

Lidocaine hydrochloride

Dibucaine hydrochloride

Anti-Inflammatory Agents

Hydrocortisone

Hydrocortisone acetate

Betamethasone valerate

Triamcinolone acetonide

Fluocinonide

Dexamethasone

Methylprednisone acetate

Antibiotics

Clindamycin

Erythromycin

Meclocycline sulfosalicylate

Tetracycline

Cholohexidine

Neomycin

Polymixin B sulfate

Bacitracin

Sulfadizine

Antifungal Agents

Clotrimazole

Miconazole

Nystatin

Acyclovis

Interferon

Vidasabine

Betadine

Miscellaneous Topical Agents

Salicylic acid

Isotretinoin

Aloe Vera

Alclomethazone dipropionate

Caprylic acid

Lindane

P.A.B.A.

Interferon

Aluminum Chorhydrate

EXAMPLE 7

The method for measuring percutaneous absorption of topical medications,described by McKenzie & Stoughton in Arch. Dermatol 1962; 86: 608-610and, more recently in Arch. Dermatol 1985; 121: 63-67, was used toassess the clinical effectiveness of various topical medicamentsincorporated into the film forming compositions of Example 1.

According to this method, the flexural aspect of a subject's forearmsare cleansed and approximately 10 mg of the test material is applied toa clearly marked 8 cm² area. Four formulations are evaluated on fourdifferent 8 cm² areas on each arm, totaling eight formulations persubject. The formulations are applied at 4.00 p.m. and allowed to remainin place overnight. At 8.00 a.m. the test sites are gently washed withsoap and water and read two hours after washing. The intensity ofblanching is determined on a four-point scale. Twenty subjects were usedto evaluate a panel of eight formulations, with a ventilated guardplaced over the test sites and ten subjects were used to evaluate theformulations with no guard placed over the test sites. The formulationstested were:

Formulation of

EXAMPLE 1, plus:

1. 1% hydrocortisone

2. 0.5% hydrocortisone

3. 0.05% betamethasone dipropionate

4. 0.1% triamainolone acetonide

Commercial Cream Formulations

5. Aristocort 0.1%

6. Kenalog 0.1%

7. Hytone 1.0%

8. Hytone 0.5%

The 4-point scale utilized is:

No blanching=0

Mild blanching=1

Moderate blanching=2

Intense blanching=3

The subject's test scores for each formulation were summarized to give atotal score for that formulation.

A comparison of the scores for each formulation showed that, in allcases the formulations 1, 2, 3 and 4 provided essentially the same skinpenetration of the active medicament, with and without the guard.Further, in the case of formulations 5 and 6 the total scores were lessthan half in subjects without guards than those with guards. In the caseof formulations 7 and 8 the total scores with and without guards wereapproximately equal, but also approximately equal for formulations 1 and2 with no guard.

These results demonstrated that the in situ films containing the activeingredients (Examples 1-4) were persistent and resisted displacement byabrasion, rubbing, etc., overnight and that the active medicamentstherein were effectively transferred to the underlying tissue.

EXAMPLE 8

The ability of the film forming compositions of Example 1 to carry andeffectively release antibiotics was demonstrated by incorporating 1%neomycin therein. This formulation was compared to a commercial 1%neomycin cream by applying the formulations to hairless mouse skins (10replications) and agar plates (4 replications) inoculated with staph.aureus. The radius of inhibitions (mm) of each replicate were summed togive a total score for each formulation. The results were:

    ______________________________________                                        Plate               Mouse Skin                                                                              Agar                                            ______________________________________                                        Film forming composition                                                                          11        49                                              of example 1 plus 1.0%                                                        Neomycin                                                                      Commercial 1% Neomycin                                                                             7        47                                              Cream                                                                         ______________________________________                                    

EXAMPLE 9

The following compositions are preferred for use in the oral cavity astopical anesthetics.

    ______________________________________                                                         % wt.                                                        ______________________________________                                        Lidocaine hydrochloride                                                                          4.0                                                        Deionized Water    10.0                                                       Tannic Acid        7.0                                                        Propylene glycol   5.0                                                        Boric Acid         1.0                                                        SDA Alcohol        68.0                                                       Salicylic Acid     2.5                                                        Hydroxypropyl cellulose                                                                          2.5                                                        Dibucaine hydrochloride                                                                          1.0                                                        Deionized Water    10.0                                                       Tannic Acid        7.0                                                        Propylene glycol   5.0                                                        Boric Acid         1.0                                                        SDA Alcohol        71.0                                                       Salicylic Acid     2.5                                                        Hydroxypropyl cellulose                                                                          2.5                                                        ______________________________________                                    

EXAMPLE 10

When tested as in Example 7, a composition containing hydrocortisoneacetate is as effective as those of Example 7 containing hydrocortisone.

The composition consists of:

    ______________________________________                                                         % wt.                                                        ______________________________________                                        Hydrocortisone acetate                                                                           1.0                                                        Deionized Water    10.0                                                       Tannic Acid        7.0                                                        Propylene glycol   5.0                                                        Boric Acid         1.0                                                        SDA Alcohol        71.0                                                       Salicylic Acid     2.5                                                        Hydroxypropyl cellulose                                                                          2.5                                                        ______________________________________                                    

This composition exhibits satisfactory shelf stability, i.e., one monthat room temperature.

Having described my invention in such terms as to enable those skilledin the art to understand and practice it, and having described thepresently preferred embodiments thereof, I claim:
 1. A liquidcomposition for in situ formation of medicament films on body tissue,comprising:(a) 0.1 to 20 percent by weight of hydroxypropyl cellulose;(b) an esterification agent which reacts with the hydroxypropylcellulose to form a reaction product which is soluble in the solvent ofparagraph (c), but insoluble in body fluids at body temperatures; (c) anon-toxic volatile solvent for said hydroxypropyl cellulose and saidreaction product; and (d) a separate medicinal component carried by saidliquid composition selected from the group consisting of hydrocortisone,hydrocortisone acetate, betamethasone dipropionate, triamainoloneacetonide, lidocaine hydrochloride, dibucaine hydrochloride.
 2. Acomposition of claim 1 in which said medicinal compound ishydrocortisone.
 3. A composition of claim 1 in which said medicinalcompound is hydrocortisone acetate.
 4. A composition of claim 1 in whichsaid medicinal compound is betamethasone dipropionate.
 5. A compositionof claim 1 in which said medicinal compound is triamainolone acetonide.6. A composition of claim 1 in which said medicinal compound islidocaine hydrochloride
 7. A composition of claim 1 in which saidmedicinal compound is dibucaine hydrochloride.